tbuckley/cabot-search huggingface dataset:
RTID-02. A PHASE 1, SAFETY LEAD-IN AND RANDOMIZED, OPEN-LABEL, PERIOPERATIVE STUDY OF VORASIDENIB COMBINED WITH PEMBROLIZUMAB IN RECURRENT OR PROGRESSIVE ENHANCING IDH-1 MUTANT ASTROCYTOMAS: TRIAL IN PROGRESS
Authors: Patrick Wen, Ingo Mellinghoff, Jennifer Clarke, Vinay Puduvalli, John de Groot, Hua Liu, Adriana Tron, Michael Chisamore, Lori Steelman, Islam Hassan, Timothy Cloughesy
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Astrocytomas are a subset of diffuse gliomas defined by intact 1p and 19q arms. Isocitrate dehydrogenase 1 mutations (mIDH-1) occur in ~70% of grade 2/3 gliomas, leading to accumulation of 2-hydroxyglutarate (2-HG). Vorasidenib (VOR) is an oral, brain-penetrant dual inhibitor of mIDH1/2 enzymes being investigated in a phase 3 study in non-enhancing gliomas. In an ongoing perioperative study in grade 2/3 gliomas, treatment with VOR was associated with interferon (IFN) signaling activation and increased T-cell infiltration, suggesting adequate 2-HG suppression renders the tumor immune microenvironment for immune checkpoint blockade, and supporting investigation of VOR in combination with an anti-programmed cell death (PD-1) antibody such as pembrolizumab in recurrent IDH-mutant gliomas treatment. This study will evaluate the safety and tolerability of VOR plus pembrolizumab to determine the recommended combination dose (RCD) of VOR, and evaluate CD3+ T-cell infiltration in tumors following preoperative treatment with the combination or VOR. METHODS This study will enroll ~70 patients with recurrent or progressive Grade 2/3 mIDH-1 astrocytoma. Key eligibility: enhancing disease, mIDH1-R132H, Karnofsky Performance Status ≥70, eligible for resection (perioperative phase only). Safety lead-in: Cohort 1 (Nf~6): VOR 40 mg QD plus pembrolizumab 200 mg Q3W in 21-day cycles. Based on DLT evaluation, cohort 2 may enroll an additional ~6 patients at VOR 20 mg QD plus pembrolizumab 200 mg Q3W. Randomized, perioperative phase (Nf~60): randomized 1:1:1 to the combination, VOR 40 mg QD, or untreated for 4 weeks preoperatively; all patients can opt to receive the combination postoperatively. Primary objectives: safety and tolerability, and VOR RCD with pembrolizumab; CD3+ T-cell infiltration in resected tumors following presurgical treatment with the combination compared to untreated tumors. Secondary objectives include clinical activity, VOR PK in tumor and blood, 2-HG concentration in tumors, and overall survival. This study will be active in the United States.
NIMG-57. NON-INVASIVE DIAGNOSIS OF IDH-MUTANT BRAINSTEM GLIOMAS
Authors: Marina Kushnirsky, Sunitha Thakur, Matthias Karajannis, Tejus Bale, Marc Rosenblum, Rachna Malani, Igor T Gavrilovic, Lauren Schaff, Elena Pentsova, Christian Grommes, Nelson Moss, Sameer Farouk Sait, Katherine Hill, Alexandra Miller, Ingo Mellinghoff, Robert Young, Andrew Lin
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Treatment of brainstem tumors is often initiated without a tissue diagnosis due to the risk of biopsy. A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 (IDH) mutation, which predicts response to alkylator chemotherapy and IDH inhibitors; non-invasive diagnostic tests are needed to identify these mutations. METHODS We identified a cohort of patients with IDH-mutant brainstem gliomas through chart review of patients who underwent magnetic resonance spectroscopy (MRS) and/or brain biopsy. IDH mutation was established by biopsy, presence of a 2-hydroxyglutarate (2HG) peak on MRS, or identification on cerebrospinal fluid (CSF) sequencing of cell-free DNA (cfDNA). RESULTS We identified 15 patients with IDH-mutant brainstem gliomas, age range 5-48, 47% women. 15/15 were involving/abutting the brachium pontis, and 10/15 were non-enhancing at diagnosis. 13/15 patients were identified by biopsy, 1/15 by MRS and CSF, and 1/15 by MRS only. 10/13 patients with available data had a non-IDH1 R132H mutation in IDH1/2. 7/7 patients with MRS prior to radiation had a 2HG peak (MRS was concordant with tissue in all cases in which biopsy was obtained). 4/6 patients with MRS post-radiation retained a 2HG peak. 4 IDH-mutant tumors had sequencing of cfDNA and an IDH mutation was found in 2/4. Response data was available in 13/15 patients; all received radiation, 10 with concurrent temozolomide: best response was partial response in 8 and stable disease in 5. 4 patients received an IDH inhibitor: 2 patients after progression, and 2 as maintenance after radiation/temozolomide, achieving tumor control in all. For this cohort, median PFS was 71.4 months and median OS has not been reached. CONCLUSION IDH-mutant brainstem gliomas have a characteristic appearance, a high response rate to treatment, and a better overall prognosis than other brainstem tumors. MRS and CSF cfDNA sequencing allow for non-invasive diagnosis of IDH mutations in these patients.
NCMP-17. PLASMA EXCHANGE FOR IMMUNE CHECKPOINT INHIBITOR INDUCED ACUTE DEMYELINATING POLYNEUROPATHY REFRACTORY TO IVIG
Authors: Avinash Kolli, Yolanda Pina, Edwin Peguero, Tyra Gatewood, Sepideh Mokhtari, Neha Verma
Journal: Neuro-Oncology (2022)

Abstract The use of immune checkpoint inhibitors in the treatment of cancer has gained prominence due to their effectiveness. Unfortunately, neurological immune-related adverse events represent a growing problem in neuro-oncology practice. Many of these cases are rare and their diagnoses and management can be challenging. We present a case of a 69-year-old male with urothelial carcinoma status post left nephrectomy who developed bilateral lower extremity weakness that began following his first dose of Atezolizumab. After three doses, his lower extremity weakness worsened to the point where he could not walk. A NCV study was performed and was consistent with acute demyelinating polyneuropathy. A cervical MRI (Magnetic Resonance Imaging) showed an enhancing lesion at C6-C8. He was treated with three days of intravenous methylprednisolone every six hours for three days followed by three days of 0.4gm/kg IVIG. He regained his ability to walk after IVIG treatment. The enhancing lesion noted on MRI remained. Three weeks after the first IVIG treatment, he declined significantly, redeveloping symptoms where he could not ambulate and required assistance to use the toilet. He had no lower extremity reflexes and had loss of proprioception of his hands. He was scheduled for another IVIG infusion at .4gm/kg followed by a dose of IVIG .6gm/kg the next day, and then four more days of IVIG .25gm/kg. His lower extremity weakness and difficulty walking remained so he was arranged for plasmapheresis x five cycles. His weakness improved, reflexes returned, and he no longer had proprioceptive loss of his hands. A cervical MRI obtained one month after plasma exchange showed resolution of the C6-C8 enhancing lesion. He is now ambulating with a cane. This case highlights the effectiveness of plasma exchange in a case that was refractory to IVIG
TMIC-21. THE ROLE OF CLEC5A ON M2-LIKE TUMOR-ASSOCIATED MACROPHAGES POLARIZATION AND DISEASE PROGRESSION IN GLIOBLASTOMA
Authors: Jiabo Li, Xuya Wang, Steven Markwell, Tatiana Carneiro-Lobo, Cheryl Olson, Ling-Kai Shih, Luqing Tong, Xuejun Yang, Daniel Brat
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma, IDH-wildtype (GBM, WHO grade 4) is the most common primary intracranial malignant tumor of adults and is characterized by an immunosuppressive tumor micro-environment (TME) and poor clinical outcomes. CLEC5A is a protein-coding gene involved in inflammatory and infectious diseases, where its activation enhances immune response. However, its role in GBM immune regulation is unclear. Seurat analysis of scRNA-seq data and CIBERSORTx analysis of GBM RNA-seq data showed that M2-like TAMs accounted for the largest proportion of immune cells in the GBM TME. Among CD163+ cells (M2-like TAM marker) in GBM, CLEC5A expression was most highly associated with overall patient survival. IHC on tumor microarrays (TMA) and analysis of Ivy GAP data indicated that CLEC5A and M2-like TAMs were preferentially expressed in tumor peri-necrotic zone. THP-1 cells exposed to GBM conditioned media showed increased CLEC5A and CD163 expression by RT-qPCR and Western blot compared to other immune-activating factors (IL-4, IL-13). CLEC5A overexpression in THP-1 cells enhanced their migration toward glioma cells in vitro, and also led to increased M2-like TAM biomarker expression. Cytokine antibody microarray results revealed that overexpressing CLEC5A in THP-1 cells also significantly increased the expression of IL-1β, IL-4, IL-6, IL-8, IL-10, IL-13, GM-CSF, and other cytokines, which all contribute to the immunosuppressive TME. In TCGA GBM data, tumors with higher CLEC5A expression were enriched in IL6-JAK-STAT3 signaling. In vivo, silencing CLEC5A delayed glioma growth and prolonged survival of tumor-bearing mice, and analysis of tumors showed reduced expression of CLEC5A, CD163 and Ki-67. Collectively, CLEC5A is expressed by M2-like TAMs and enhances M2-like TAM polarization, likely through IL6-JAK-STAT3 signaling.
MODL-06. ASSESSMENT OF ONCOLYTIC VIRUS SPECIFICITY AND CYTOTOXICITY IN A HYBRID GLIOBLASTOMA-CEREBRAL ORGANOID MODEL
Authors: Rodolfo Sanches Ferreira, Bruno H S Araujo, Oswaldo Okamoto
Journal: Neuro-Oncology (2022)

Abstract Recent studies have demonstrated potent oncolytic effects of wild-type Zika virus (ZIKV) against primary central nervous system (CNS) tumors, including Medulloblastoma, Atypical Teratoid/Rhabdoid Tumor (AT/RT), and Glioblastoma (GBM). However, the neurotropism of ZIKV urges further evaluation of specific tumor-targeting properties and comparative toxicity to non-neoplastic neural cells in order to address its therapeutic potential. We have developed a hybrid organoid model by co-culturing GBM cells with mature human cerebral organoids and assessed cytotoxicity of the Brazilian ZIKV isolate (ZIKVBR) towards normal brain organoid cells and GBM cells. Human induced pluripotent stem cells (hiPSC)-derived cerebral organoids were co-cultured with 105 GFP-expressing cells of three different GBM cell lines. A total of 20.000 PFU of ZIKVBR or mock condition was added per co-cultured model. Viable cells were analyzed by flow cytometry (FC) and fluorescence microscopy at different time points. ZIKVBR presence was assessed by PFU assay. Although ZIKVBR infection did not cause a pronounced reduction of GFP+ cell proportion over time in all GBM cell lines, cell viability analysis showed a greater amount of non-viable GFP+ cells over GFP- cells in all ZIKVBR-treated groups, compared to their corresponding mock groups. PFU assays of cell culture supernatants confirmed the presence of infectious viral particles in treated groups and absence in mock groups. Our data reveal that ZIKVBR has a potential oncolytic effect characterized by preferential killing of GBM tumor cells over normal cerebral cells, in a hybrid organoid model. These findings support the development of an oncolytic virus therapy platform based on ZIKV.
TMIC-06. ANTAGONISM OF DRD2 USING ONC201 INCREASED EXPRESSION OF ANTIGEN PRESENTATION PATHWAY PROTEINS IN DIFFUSE MIDLINE GLIOMA, RECRUITING TUMOR INFILTRATING LYMPHOCYTES IN VIVO
Authors: Mika Persson, Evangeline Jackson, Ryan Duchatel, Liesl Bramberger, Holly McEwen, Padraic Kearney, Izac Findlay, Alicia Douglas, Birgit Kobbe, Raimund Wagener, Martin Larsen, Pouya Faridi, Jeff Holst, Jemma Mayall, Craig Gedye, Hubert Hondermarck, Jay Horvat, Brett Nixon, Rodrigo Cartaxo, Carl Koschmann, Fatima Valdes-Mora, David Gallego Ortega, Javad Nazarian, Marta M Alonso, Esther Hulleman, Jasper Van der Lugt, Nicholas Vitanza, Sabine Mueller, Matthew Dun
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG) is a high-grade glioma with a median overall survival of 9-11 months. Radiotherapy is the only recognized treatment. The DMG tumor microenvironment (TME) contains few, if any, tumor infiltrating lymphocytes (TILs) or inflammatory cytokines, thus is distinctive of an ‘immunologically cold’ tumor/TME.1 DMG lack the expression of immunosuppressive immune checkpoint proteins, likely explaining the failure of immune checkpoint inhibitors (ICI) tested under clinical trials for DMG patients, and suggestive of an alternative mechanism underpinning the cold TME. 1 Glioblastomas also harbor a cold TME, which can be somewhat explained by T cell lymphopenia, influenced by the sequestration of T cells in the bone marrow (through Beta-arrestin-induced internalization of Sphingosine-1-phosphate receptor 1 [S1PR1]). 2 Dopaminergic activation of Beta-arrestin and hence S1PR1 internalization, is potentially regulated through dopaminergic peripheral nerves in primary and secondary lymphoid organs, regulated by the Dopamine receptor D2 (DRD2), that is highly expressed on T cells. ONC201 is a potent DRD2 antagonist, currently in phase I-III clinical trials for DMG patients, alone and in combination with radiotherapy and the PI3K/AKT inhibitor paxalisib (NCT05009992). Proteomic profiling of DMG patient-derived cells +/-ONC201 showed increased expression of several antigen presenting pathway proteins, including Beta-2-microglobulin (B2M) and HLA class I histocompatibility antigen, A alpha chain (HLA-A). This was confirmed in vivo using SU-DIPG-VI patient-derived xenograft mouse model tissues +/-ONC201 alone, and together with paxalisib. Excitingly, this combination (given orally) promoted the recruitment of TILs to the tumor, revealing novel immunomodulatory effects. In vivo, ONC201 promoted the expression of EMILIN-3, a TGF-β antagonist that is known to inhibit HLA-A/B2M expression, possibly explaining the increased MHC-I activity. This study uncovers a novel link between treatment of DMG with ONC201 and paxalisib and the role dopaminergic peripheral nerves signaling may play on the sequestration of T cells within lymphoid organs and lymphopenia.
CNSC-22. IDENTIFICATION OF MECHANISMS INVOLVED IN THE RECURRENCE OF GLIOBLASTOMA BY TRANSCRIPTOMIC, PROTEOMIC AND SPATIAL PROFILING ANALYSIS
Authors: Tala Shekarian, Marie-Françoise Ritz, Tomas A Martins, Sabrina Hogan, Philip Schmassmann, Bettina Burger, Gregor Hutter
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and common brain tumor. Despite multimodal therapy which consists of complete tumor removal, chemo- and radiation therapy in most patients, the tumor recurs, and the overall survival of only 14 months remains very poor. To identify tumor-induced immune evasion and treatment resistance mechanisms induced during GBM recurrence, we aimed at characterizing the immunological/molecular changes in patient-matched treatment-naïve and recurrent GBM samples. MATERIAL AND METHODS Proteins and total RNA were extracted from 16 patient-matched treatment-naïve (primary) and recurrent GBM fresh frozen tumor samples. The expression of genes involved in brain immune responses were compared using Nanostring panels encompassing Cancer and Neuroinflammation genes. Proteomic was conducted using 6 patient-matched primary and recurrent tumor samples. Immunostaining was performed on a tissue microarray containing matched primary and recurrent tumor samples to identify tumor cells and microglia in order to assess spatial transcriptome of these specific cell types in situ using GeoMX technology. Moreover, correlation analysis of differentially genes and proteins with time to relapse was performed. RESULTS Genes significantly differentially expressed between primary and recurrent tumors revealed genes overexpressed in recurrent tumors belonging to “FCGR-mediated Phagocytosis” and “synapse pruning” pathways. Proteomic confirmed the synaptic signalling considering overexpressed proteins. Correlation studies with the time to relapse indicated that higher expression of FCG receptors, complement molecules and synaptic components correlate with shorter time to relapse, sharing similarities with neurodegenerative/cognitive disorders such as schizophrenia and Alzheimer disease. The source for these molecules is under evaluation with the spatial transcriptomic analysis. CONCLUSION Upregulation of specific proteins such as FCG receptors, complement and synaptic components may result in more favourable conditions for tumor regrowth and may therefore be identified as negative predictors patient outcome. Interfering with these molecules may represent novel therapeutic options after initial GBM surgery.
EXTH-63. COMBINED INHIBITION OF TOP1 AND PARP: A NOVEL THERAPEUTIC STRATEGY FOR GBM WITH PTEN DEFICIENCY
Authors: Olga Kim, Madison Butler, Robert Robey, Raj Chari, Zach Sergi, Meili Zhang, Ying Pang, Guangyang Yu, Wei Zhang, Hua Song, Dionne Davis, Herui Wang, Mythili Merchant, Alice Ranjan, Mark Gilbert, Michael Gottesman, Yves Pommier, Jing Wu
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive and lethal type of brain tumor. Activation of PI3K/mTOR pathway along with the loss of its primary negative regulator, phosphatase and tensin homolog (PTEN), occurs in nearly 50% of GBM patients. As PTEN is known to promote DNA damage repair deficiency, here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. METHODS We used patient-derived GBM cells and stem-like cells to determine response to LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor, and the PARP inhibitors Olaparib or Niraparib. Treatment efficacy was also determined using cell viability, cell cycle, DNA damage, repair, and apoptosis assays in a pair of isogenic PTEN-null and PTEN-WT glioma cell lines derived from a genetically engineered mouse GBM model. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. RESULTS PTEN-deficient cells are highly sensitive to LMP400 and PTEN rescue lessens sensitivity to the treatment. Combining LMP400 with PARP inhibitors, Olaparib or Niraparib, leads to synergistic cytotoxicity. LMP400/Niraparib combination induces G2/M cell cycle arrest, DNA damage, suppression of homologous recombination (HR)-related proteins and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to isogenic PTEN-WT cells. Gene set enrichment analysis revealed suppression of cell cycle and DNA damage repair as well as activation of cell death pathways. Finally, CRISPR-Cas9 KO screening suggests that LMP400 is not likely to be a substrate for ABC transporters, suggesting the brain penetration and supporting the use in brain tumor patients. CONCLUSION Combined inhibition of TOP1 and PARP induces synergistic antiglioma effects selectively in PTEN-null glioblastoma cells, providing a strong scientific premise for a clinical trial of combined treatment with LMP400 and Niraparib in a subset of GBM with PTEN deficiency.
RADT-34. ANALYSIS OF A METHYLATION CLASS-GUIDED RADIOTHERAPY IN MENINGIOMA PATIENTS - AND THE PROSPECTIVE PHASE II MARCIE TRIAL WITH CARBON-ION BOOST RADIOTHERAPY
Authors: Maximilian Deng, Felix Hinz, Philipp Sievers, Tanja Eichkorn, Kraemer Anna, Meixner Eva, Sandrini Elisabetta, Hoerner-Rieber Juliane, Harrabi Semi, Seidensaal Katharina, Unterberg Andreas, Antje Wick, Wolfgang Wick, Andreas von Deimling, Stephanie Combs, Herfarth Klaus, Debus Juergen, Felix Sahm, Koenig Laila
Journal: Neuro-Oncology (2022)

Abstract Meningiomas represent the most common primary brain tumor type, with a recurrence rate of approximately 20% following resection. Classification by molecular classes was demonstrated to be more accurate in identifying patients at high risk of disease progression in meningiomas, compared to WHO grading only. Novel radiotherapeutic modalities using protons or carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, enabling a higher local dose deposition while reducing the radiation dose for organs of risks. The prospective single-arm phase II - MARCIE trial investigated a bimodal radiotherapy using photons (50 Gy in 25 fractions) and a carbon-ions boost with 18 Gy (RBE) in 6 fractions. Local progression-free survival after 3 years was defined as primary endpoint. In total, 33 patients were recruited before termination of the trial. After 3 years, local progression free survival was estimated at 94.7% and overall survival at 89.8%. Serious adverse events in the form of radiation necrosis were observed in 3 cases, requiring a subsequent treatment with bevacizumab. Post-hoc DNA methylation profiling revealed that relapses occur more frequently in high-risk meningiomas following radiotherapy, compared to the intermediate risk-group, confirming the prognostic relevance of the methylation-based meningioma classifier.Subsequently, a retrospective matched-pair analysis was performed to compare irradiated (n &amp;gt; 100) and non-irradiated meningiomas, stratified into the molecular risk groups (ben, int, high). The clinical benefit of postoperative radiotherapy and dose escalation with regard to the local control are currently being assessed for the respective molecular meningioma classes. Postoperative, bimodal radiotherapy with carbon-ion boost represent an auspicious treatment modality with an excellent local tumor control following resection. Molecular risk stratification is crucial in identifying patients who might benefit from postoperative radiotherapy.
BIOM-06. IDENTIFICATION OF AN INFLAMMATORY BIOMARKER SIGNATURE IN PLASMA-DERIVED EXTRACELLULAR VESICLES OF GLIOBLASTOMA PATIENTS
Authors: Georgios Giamas, Chiara Cilibrasi, Thomas Simon, Nicolas Stewart, Giles Critchley, Murat Eravci
Journal: Neuro-Oncology (2022)

Abstract Diagnosis of Glioblastoma (GBM) remains a clinical challenge, currently relying on symptomatic presentation of the tumour, brain imaging and invasive biopsy. Description of effective biomarkers in biofluids could prove invaluable in GBM diagnosis. Extracellular vesicles (EVs) are essential to intercellular crosstalk in the tumour bulk and circulating EVs have been described as a potential reservoir of GBM biomarkers. Our work focuses on the: (i) isolation of EVs from blood liquid biopsies of GBM patients. (ii) Characterisation of their transcriptomic and proteomic cargoes to identify/validate novel candidate GBM biomarkers that could improve GBM diagnosis/prognosis. (iii) For cases where the original GBM tumour tissues are available, we will examine the expression of the identified biomarker signatures (derived from blood-EVs) to see if the content of EVs mirrors the transcriptomic/proteomic profile of the original tissue. Similar comparisons will be performed in GBM cohorts available in TCGA. Ultimately, in future studies, transcriptomic/proteomic analyses will be assessed during patients’ follow-ups to correlate the observed biomarker profiles with MRI data,treatment,recurrence, including molecular and clinical features.Our preliminary data comparing the proteomic cargoes of EVs derived from GBM patients (n=15) and those from healthy volunteers (n=10) indicated the presence of a GBM inflammatory biomarker signature comprising members of the complement and regulators of inflammation and coagulation. Bioinformatic analysis highlighted that all potential markers exclusively identified in patient samples have been linked with either GBM diagnosis,prognosis or associated signalling, suggesting that sEVs protein cargo could mirror the landscape of the original tumour and that selective circulating sEV-derived proteins might be used as hallmarks for GBM patients.Overall, this study is a step forward in the development of a non-invasive liquid biopsy approach for the identification of valuable biomarkers that could significantly improve GBM diagnosis and, consequently, patients’ prognosis and quality of life.